Role of histone modifications in melanoma progression and association with oxidative stress

• Grant number: 24/20461-7
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: August 01, 2025
• End date: March 31, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Miriam Galvonas Jasiulionis
• Grantee: Gabrielle do Nascimento Sividanes
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Melanoma is a tumor originating from melanocytes and is characterized by its aggressiveness, lethality, and high metastatic potential. Its high plasticity, proliferative capacity, and adaptability present a significant challenge in treating this disease. Both malignant transformation and tumor heterogeneity result from the accumulation of mutations and epigenetic modifications that culminate in the altered expression of proteins that control cell division, cycle, and differentiation. The most studied epigenetic mechanisms are DNA methylation and post-translational modifications of histones (PTMs). In addition to their role in DNA packaging, histones actively regulate gene expression, DNA replication, and repair via PTMs in their N-terminal regions. Histone PTMs are highly dynamic, allowing chemical groups to be added or removed by the action of specific enzymes. The most studied histone PTMs are acetylation and methylation of lysines, with the enzymes responsible for adding these groups being histone acetyltransferases (HATs) and lysine methyltransferases (KMTs), respectively. The removal of these molecules is performed by histone deacetylases (HDACs) and lysine demethylases (KDMs). These enzymes often exhibit dysregulated expression in tumors, resulting in changes in chromatin conformation and, consequently, in gene expression. In the mouse model of melanoma progression developed in the laboratory, malignancy signatures were identified (associated with a decrease in H4K5ac and H4K8ac marks), epithelial-to-mesenchymal transition (EMT) (associated with a decrease in H4K20me2 and H4K20me3 marks), and metastasis (associated with a decrease in H3K36me2 and H3K36 marks). However, it is still unclear which genes are regulated by these epigenetic alterations and what the role of these PTMs is in melanoma progression. Histone-modifying enzyme inhibitors hold promise for epigenetic cancer therapy. Despite drugs such as Vorinostat (an HDAC inhibitor) already being used in the treatment of some types of tumors, inhibition of these enzymes has proven insufficient as monotherapy. Data show that the antitumor effect of these compounds is associated with DNA damage caused by increased oxidative stress. An intrinsic feature of tumors is the overproduction of reactive oxygen species (ROS). This phenomenon occurs due to high mitochondrial metabolism, which is necessary to sustain the high proliferation rate and generate aberrant redox signaling, which is partly responsible for the tumor phenotype. However, ROS can cause damage by reacting with proteins, DNA, and membranes, leading to cell death. In response to stress, tumor cells increase the expression of antioxidant enzymes. Regulation of the antioxidant defense is associated with resistance to chemotherapeutic agents that increase oxidative stress. Through previous studies, our research group identified that some histone PTMs are linked to malignancy, epithelial-to-mesenchymal transition, and metastasis characteristics in the mouse model of melanoma progression established in our laboratory. It was also found that, in addition to oxidative stress being essential for the malignant transformation of melanocytes in our model, the antioxidant enzymes NQO1 and the Prx-Trx-TrxR system show altered expression throughout tumor progression. Therefore, the objectives of this study are to evaluate the role of the studied epigenetic marks in the malignant progression of our mouse melanoma model, as well as combine epigenetic therapy with inhibition of antioxidant enzymes and assess the effect of the treatment in vitro (in murine and human cells) and in vivo. In doing so, we aim to study the relationship between epigenetics and oxidative stress in melanoma, with the goal of exploring new therapeutic alternatives for the disease.